Process fob the demethylation of



'2,3',5,6-chromone in small yield.

Patented Jan. 19, 1954 PROCESS FOR THE DEMETHYLATION OF METHOXY DERIVATIVES F FURO 4,5',-

6,7-CHROMONES Nasry Badran, Heliopolis,

to The Memphis Chemical Co., Cairo, Egypt,'an

Egyptian company Cairo, Egypt, assignor No Drawing. Application October 23, 1951, Serial No. 252,795

Claims priority, application Great Britain December 15, 1950 9 Claims. (01. zoo-345.5)

This invention relates to a process for the demethylation of methoxy derivatives of furo- 4,5,6,7-chromones.

Several methoxy furo-4',5',6,7-chromones oc-.- our in nature. Khellin, a major constituent of the alcohol extract of Ammi visnaga seeds, is 5,8-dimethoxy-furo 4,5',6,'7 methylchromone. Visnagin likewise occurs in the seeds of this plant, and is 5-methoxy-furo-4',5',6,'7-methylchromone.

The compounds in which the methoxyl groups of visnagin and. khellin are replaced by hydroxyl groups are useful as drugs and as intermediates in the preparation of therapeutically active substances. These substances can be obtained by demethylation of khellin and visnagin and processes accomplishing this have therefore recently been the subject of considerable research. However, a demethylation process which might be applied commercially has not heretofore been available.

Clarke and Robertson, J. Chem. Soc., 1949, 302,

have reported attempts to prepare dihydroxy furan chromone from khellin, employing boiling hydriodic acid freshly distilled over red phosphorus. The aqueous hydriodic acid solution,

specific gravity 1.7, is added to a mixture of khellin in acetic anhydride and the resulting SO? lution refluxed for one-half hour. However, only a resinous product was obtained which apparent- 1y contained a mixture of a large number of substances, of which only isokhellin was isolated. Clarke, Glazer and Robertson, J. Chem. Soc., 1948, 2260, refluxed visnagin with concentrated hydriodic acidin the presence of acetic anhydride, but obtained 7-hydroxy-2-methyl furan- Schonberg and Sina, J. Am. Chem. Soc., 72, 3396 (1950), ob tained 5,8-dihydroxy- 2 methylfuro-4',5,6,7- chromone by a complicated process. Khellin was heated with magnesium iodide in an ether-hen: zene solution. The solvent wasremoved in vacuo and the residue dried in the vacuum at 130 C. and then kept at 160 to 165 C. for 1 hours. The solid was cooled, pulverized and decomposed with dilute sulfuric acid. No yield was given.

In contradistinction to these processes, the process of this invention accomplishes the demethylation of fi-methoxy derivatives of furo- 4,5,6,7-chromones in good yield, is simple, straightforward and can be applied on a commercial scale.

According to the invention, S-methoxy furo- ',5',6,7-chromones are treated at an elevated temperature with an aqueous solution of a halogen acid. The reaction proceeds at a temperature in the range from C. to the reflux temperature of the aqueous acid solution and is complete in a comparatively short time, usually within one hour or less. Higher temperatures up to about 150 C. can be used if refluxing is carried out under pressure. The yield usually is over 80% and may be nearly quantitative under carefully controlled conditions.

The invention is applicable to the demethyla-v tion of 5-methoxy compounds of the following general formula:

OCHa

where R. is hydrogen, or a methoxyl group, R is hydrogen and. R." is selected from the group consistingof hydrogen, alkyl, such as methyl,

The reaction which occurs may be represented where R, R, and R" are as defined above and group demethylation nonetheless occurs only at The acid should be a halogen acid, i. e., hydrochloric, hydrobromic or hydriodic acid, and HK in the above equation represents such acids. The aqueous solution of the acid may contain from 10% to of the acid by weight, although the concentrated acid may be used as such if the reaction time is not too long and thelower temperatures, i. e., below the reflux temperature, are used.

The following examples'illustrate the process of the invention.

Example 1 Visnagin (1.0 gram), 15 cc. of hydrochloric acid (specific gravity 1.8) and 15 cc. of distilled water were refluxed under a water condenser for one hour. Visnagin dissolved in the reaction mixture, and after about 20 minutes a precipitate began to form, increasing gradually in amountr The mixture was allowed to cool to room temperature and then filtered. A crystalline product weighing 0.8 gram was recovered. This represents a yield of approximately 55%. This was recrystallized from' gl'acial acetic were, giving almost colorless crystal's having a melting point of 156-158 C.

Analysis: Calculated for Cizl-laQ C, 66.66

3.7. Found: C, 66.71; H, 3.83;

This shows that the reaction proceeded according to thefollowing equation:

Example 2 Example 1 is reheated, employing cc. of hydrobromic acid (specif c gravity 1.46)." An 85% yield is obtained of the 5-hydroxyfuro-fl',5,'- 6 ,7- rne'th'yl" chromone.

l Erample v3 Example 1 is repeated, employing 5 cc. of 54% hydriodic acid. An 85% yield of the 5-hydr0xyfuro-4, 5, ,7-methyl'chromone is obtained.

' Example 4 Khellin (1.0 gram), cc. of hydrochloric acid (specific gravity 1.08) and )5 cc. of distilled water were refluxed. The chromone dissolved in the reaction mixture and after about minutes a precipitate formed, which increased gradually in amount. After no further precipitate formed, the reaction was halted and the mixture allowed to OOH; I H C WL+ 93 0/ CH3 HCl OR: I o 4 0 0 Q C Ha Exarriple 5 E m l 4 i rep at d emp oyin 0 c of hydrohromic acid (specific gravity 1.46) An approximately 85% yield-of the 5 hydroxy B-meth oxy-iuro- LQS",efi-chromoneis obtained.

' Example 6 Example 4 is repeated, employing 5 cc. of 54% hydriodicacid. *An approximately 85% yield of the' 5-hydroxy '8-methoxy-furo-4',5",6,7-methyl chromone is obtained.

. 40 cool to room temperature. The reaction required The term "consists essentially in means that the reaction is carried out in the absence of material which would interfere with it, such, for instance, as acetic anhydride, but the term does not exclude non-interfering substances not mentioned in the claims.

I claim:

:1. '{A' process of preparing 5-hydroxy tum-4'5,- 6,7"-c'hromon'es from the corresponding methoxy derivatives, which consists essentially in heating ithmhrorhone'fw'itli an aqueous solution of an inorganic halogen acid at a temperature within therar'ige from '70 to 150 C. at which the reactionprcceeds."

7 ""2JA process of preparing 5-hydroxy furo- 4.',5f,6,.'.7-chromon es from the corresponding methpxy derivativesfwhich consists essentially in heating the chromone with an aqueous solution of an inorganic' halogen acid at reflux temperature within the range from .70 to 150 C.

processpf preparing B-hydroxy furo- 4",'5',5,7-chromones from the corresponding methoxy derivatives, which consists essentially in heating thechroino'ne withan aqueous solution" of hydrochloric'acid at a temperature within the range from to Cat'which' the reaction proceeds. ""4: A" process of preparing 5-hydroxy furol;5',"6,'7-chromones from the corresponding methoxy derivatives, which consists essentially in heating the chromone'witnan aqueous solution of hydrobromicacid at a temperature within the rangdfroniTO to 150" C. at which the reaction proceeds. *5. A process of preparing fi-hydroxy furo- 4,5',6,'7-"chrornorie's from the corresponding methoxy derivatives, which consists'essentially in heating the 'ch'romone with 'an aqueous solution'of l ydriodic acid at a temperature within the ra ge from 70 "to150"C.' a't'whic'h the'reaction" proceeds.

6. A process for preparing a 5-hydroxy-furoi',5, 6;7-chro:mone which consist "essentially in heating '5- methoxyfuro-4,5",5,7-chromone with an aqueous solution of an inorganic halogen acid at a temperature within the range from 70 to 150" C. at which" deinethylation occurs, whereby the methoxyl group in the 5'-p0sition is replaced bythe hydroxyl' group.

'7. A process in accordance with claim 6 in which the inorganic acid ishydrochloric acid and the chromone is "visnagin;

8. A process of preparing a .5-hydroxy-8- methoxyfuro-fl';5',6,7-chromone, which consists es sentially in heating a 5, 8-dimethoxy-furo-4',5,- 6,7-chromone with an aqueous solution of an inorganic halogen acid at a temperature within the range from 70 to 150 'C. at which demethylation s c-cu s. where y the m h v group a e 5- position is repl aced'.by a hydroxyl group.

9. A process in accordance with claim 8 in .hich the inorganic acid is hydrochloric acid and the chromone is khellin.

' NASRY BADRAN.

Ref r n s Ci in he o s te 

1. A PROCESS OF PREPARING 5-HYDROXY FURO-4'',5'',6,7-CHROMONES FROM THE CORRESPONDING METHOXY DERIVATIVES, WHICH CONSISTS ESSENTIALLY IN HEATING THE CHROMONES WITH AN AQUEOUS SOLUTION OF AN INORGANIC HALOGEN ACID AT A TEMPERATURE WITHIN THE RANGE FROM 70 TO 150* C. AT WHICH THE REACTION PROCEEDS. 